Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders

Abstract

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.

Keywords: blood-brain barrier disruption; glial cells; neurodegenerative disorders; neurofilament light; neuroinflammatory biomarkers; neurovascular unit; tight junction proteins.

FIGURE 1

Schematic diagram shows neuronal markers in the neurovascular unit with BBB. BBB is a dynamic structure that functions as a gatekeeper. (A) Markers in neurons in different regions. (B) neurodegeneration of dendrites, axon, synaptic area. (C) NVU is comprised of micro blood vessels, endothelial cells, BBB, pericytes, neurons, astrocytes, and microglia. (D) BBB with endothelial cells, pericytes, tight junction and adherens junctions consisting of claudin, zonula occludens (ZO-1), occuludin, junctional adhesion molecule (JAM) and cadherin that regulates BBB permeability. The presence of increased levels of these markers in the blood or CFS indicates the damage to these structures. Derangement of BBB proteins can also cause BBB dysfunction.

FIGURE 2

Schematic diagram shows microglial and astrocyte markers in normal, activated, anti-inflammatory and proinflammatory states. Microglia and astrocytes are activated in various neuroinflammatory and neurodegenerative disorders. Activated microglia and astrocytes express several markers that are also detected in biofluids. M1 microglia and A1 astrocytic phenotypes are neurotoxic and exacerbate neuroinflammation and neurodegeneration whereas M2 microglia and A2 astrocyte phenotypes are neuroprotective and protect the brain. These neurotoxic and neuroprotective glial cells express or secrete different molecules to exert detrimental or protective functions in the brain. AQ4, aquaporin 4; FGF, fibroblast growth factor; NO, nitric oxide; OPN, osteopontin; PTX3, pentraxin 3; ROS, reactive oxygen species; S100a10, S100 calcium-binding protein A10.